Methods for inhibiting fascin

Abstract

Provided are compositions and methods for treating a condition or disorder mediated by fascin activity in a subject in need thereof which method comprises administering to the subject a therapeutically effective amount of at least one compound of any one of Formula I-a to I-n, II, II-a, II-b or III or a pharmaceutically acceptable salt thereof.

What is claimed: 
     
       1. A method of inhibiting fascin expression or fascin activity, comprising administering an effective amount of a fascin inhibitor to a cell with fascin expression to thereby inhibit fascin expression or fascin activity in the cell, wherein the fascin inhibitor is a compound of Formula A: 
       
         
           
           
               
               
           
         
         or a tautomer thereof, and/or a pharmaceutically acceptable salt thereof, wherein in Formula A: 
         Y is N or CR; 
         R 1  is phenyl, 5-membered heteroaryl or 6-membered heteroaryl, wherein the phenyl, 5-membered heteroaryl or 6-membered heteroaryl is optionally substituted with 1 to 3 R 6 ; 
         R is hydrogen, halo or lower alkyl; 
         L 1  is selected from the group consisting —(C(R 8 ) 2 ) j —, —(C(R 8 ) 2 ) q —C(O)—(C(R 8 ) 2 ) r —, —(C(R 8 ) 2 ) q —C(O)N(R 8 )—(C(R 8 ) 2 ) r —, —(C(R 8 ) 2 ) q —N(R 8 )C(O)—(C(R 8 ) 2 ) r —, —(C(R 8 ) 2 ) q —N(R 8 )S(O) 2 —(C(R 8 ) 2 ) r —, —(CH 2 ) q —S(O) 2 N(R 8 )—(CH 2 ) r —, —S—, —O— and —NR 8 —; 
         j is 1, 2 or 3; 
         q is 0 or 1; 
         r is 0 or 1; 
         L 2  is selected from the group consisting a covalent bond, —C(O)N(R 8 )—, —N(R 8 )C(O)—, —N(R 8 )S(O) 2 —, and —S(O) 2 N(R 8 )—; 
         R 5  is phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl; wherein the phenyl is substituted with 1 to 4 R 2 , and the 5-membered heteroaryl or 6-membered heteroaryl is optionally substituted with 1 to 4 R 2 , wherein each R 2  is independently selected from the group consisting of lower alkyl, lower haloalkyl, —OH, —OR 7 , —SH, —SR 7 , —NR 10 R 10 , halo, cyano, nitro, —COH, —COR 7 , —CO 2 H, —CO 2 R 7 , —CONR 10 R 10 , —OCOR 7 , —OCO 2 R 7 , —OCONR 10 R 10 , —NR 10 COR 10 , —NR 10 CO 2 R 10 , —SOR 7 , —SO 2 R 7 , —SO 2 NR 10 R 10 , and —NR 10 SO 2 R 7 ; 
         each R 6  is independently selected from the group consisting of halo and lower alkyl optionally substituted with 1-3 halo; or two adjacent R 6  on a phenyl ring form a 5- or 6-membered cycloalkyl or heterocycloalkyl fused with the phenyl ring; 
         R 7  is lower alkyl; 
         R 8  is hydrogen; and 
         each R 10  is independently hydrogen or lower alkyl, or two R 10  together with the atom(s) attached thereto form a 4- to 6-membered ring, with the proviso that when R 5  is phenyl and L 2  is a covalent bond, then R 5  is substituted with 1 to 4 R 2 . 
       
     
     
       2. The method of  claim 1 , wherein the compound of Formula A is selected from the group consisting of 
       
         
           
           
               
               
           
         
         or a tautomer thereof, and/or a pharmaceutically acceptable salt thereof, 
         wherein n is 1, 2, 3 or 4, u is 1, 2 or 3, and L 1 , and R 6  are as defined in  claim 1 . 
       
     
     
       3. The method of  claim 1 , wherein R 1  is phenyl substituted with one, two, or three groups chosen from halo and lower alkyl. 
     
     
       4. The method of  claim 1 , wherein R 1  is triazole. 
     
     
       5. The method of  claim 1 , wherein L 2  is —N(R 8 )S(O) 2 —. 
     
     
       6. The method of  claim 1 , wherein L 1  is —S—. 
     
     
       7. The method of  claim 1 , wherein X 1  is OH and X 2  is O. 
     
     
       8. The method of  claim 1 , wherein R 2  is independently selected from the group consisting of OH, halo, lower alkyl, and —OR 7 . 
     
     
       9. The method of  claim 2 , wherein the compound of Formula A has the structure: 
       
         
           
           
               
               
           
         
       
       or a tautomer thereof, and/or a pharmaceutically acceptable salt thereof. 
     
     
       10. The method of  claim 1 , wherein, in the compound of Formula A, Y is N. 
     
     
       11. The method of  claim 1 , wherein, in the compound of Formula A, R 1  is a 5-membered heteroaryl or 6-membered heteroaryl optionally substituted with 1 to 3 R 6 . 
     
     
       12. The method of  claim 1 , wherein, in the compound of Formula A, L 2  is selected from the group consisting —C(O)N(R 8 )—, —N(R 8 )C(O)—, —N(R 8 )S(O) 2 —, and —S(O) 2 N(R 8 )—. 
     
     
       13. The method of  claim 1 , wherein, in the compound of Formula A, R 5  is a 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl.